Allergic reactions of the skin to various agents known as allergic contact dermatitis (ACD), is an immune response that occurs in the skin. The response is the result of the penetration of the skin by a foreign substance (e.g. hapten or antigen) that provokes a skin sensitization reaction. ACD is a two phase process involving an initial induction phase followed by an elicitation phase.
The induction phase occurs immediately after first time exposure of the skin to the hapten or antigen and is characterized by the formation of immune memory cells that can subsequently recognize the specific hapten or antigen which previously entered the skin for the first time.
The elicitation phase occurs when the skin is subsequently re-exposed to the original hapten or antigen. In the elicitation phase, the skin provides an overt reaction to the presence of the hapten or antigen in the form of a skin inflammatory response.
ACD generally results in a life-time persistent memory for the specific hapten or antigen. Thus, when the skin is exposed to the hapten or antigen at a subsequent time, there is typically an immediate and often severe skin inflammatory response.
Agents that cause allergic contact dermatitis are varied and numerous and include, for example, metals (e.g. nickel, chromium, cobalt and the like) fragrances, chemicals, cosmetics, textiles, pesticides, plastics, pollen and the like (see, for example, R. J. G. Rycroft et al. "Textbook of Contact Dermatitis"). Therapeutic agents such as drugs may also cause allergic contact dermatitis particularly when administered transdermally.
The transdermal route of parenteral delivery of drugs provides many advantages over alternate routes of administration. Transdermal delivery systems (TDS) for delivery of drugs or other beneficial agents are well-known (see, for example, U.S. Pat. Nos. 3,598,122, 3,598,123, 4,286,592, 4,314,557, 4,379,454, 4,599,222 and 4,573,995, which are each incorporated herein by reference). A TDS is generally composed of the following components: (a) "basic components", including backing, matrix reservoir, and an optional separate adhesive layer; (b) the drug or other therapeutic agent; (c) "additives", including solubilizers, plasticizers and permeation enhancers; and (d) "impurities" such as residual amounts of monomers, initiators, cross-linkers, etc., from the polymerization process during fabrication of the basic components.
However, TDS provide conditions highly conducive for the induction of skin allergic reactions, and the following skin reactions may be expected to occur:
1. Irritant reactions to the drug, an additive, an impurity, or a combination thereof; PA1 2. Allergic reactions, especially to the low molecular weight components (drug, additive, impurity, adhesive); PA1 3. Prolonged skin occlusion causes blocking of sweat ducts favoring local sweat retention syndrome. PA1 (a) a transdermal delivery system comprising a therapeutic agent (e.g. a drug) of interest; and PA1 (b) an effective amount of at least one potassium-sparing diuretic.
Allergic contact dermatitis presents a significant problem in the transdermal administration of therapeutic agents. It is well known that many drugs, including some currently marketed in the United States (e.g. clonidine) sensitize the skin when used in a transdermal delivery system. Skin inflammation may be produced not only by the transdermally delivered drug, but also by a non-sensitizing drug combined with skin sensitizing permeation enhancers, or a combination of a sensitizing drug and a sensitizing permeation enhancer. Penetration of these sensitizing agents into the skin and the resulting skin irritation may persist well beyond the time that the transdermal patch is removed from the skin. The local inflammation may be a source of discomfort and a clinical complication in a patient suffering from such a reaction.
Efforts have been made to address the problem of allergic contact dermatitis by prophylactically treating the skin to prevent the onset of the induction phase of ACD and/or to therapeutically prevent or reduce the adverse effects of the elicitation phase of ACD. For example, U.S. Pat. No. 5,202,130 discloses that lanthanide ions and organic calcium channel blockers individually can be used for the treatment of contact allergic dermatitis.
Wolfgang Diezel et al., J. Invest. Derm., Vol. 93, No. 3, pp. 322-326 (September 1989) discloses the sensitization of mice with 1-chloro-2, 4-dinitrobenzene and subsequent treatment with lanthanum citrate and diltiazem hydrochloride to prevent the onset of the induction phase of the sensitizing agent. Philip W. Ledger, et al., U.S. Pat. No. 5,120,545 disclose the prevention of skin sensitization by the administration of an antigen processing-inhibiting agent such as ammonium chloride. A method of preventing contact sensitization using steroids (e.g. corticosteroid and glucocorticoid carboxylic acid esters) is disclosed, for example, in Alfred Amkraut, U.S. Pat. No. 5,118,509 and Peter M. Ross, et al., U.S. Pat. No. 4,897,260.
Methods of treating ACD through the blocking of the elicitation phase is disclosed, for example, in John McFadden, et al., J. Invest. Derm., Vol. 99, No. 6, pp. 784-786 (December 1992). Tuberculin-induced delayed-type hypersensitivity reaction in human skin was inhibited by topical applications of verapil hydrochloride prior to or concurrent with challenge with tuberculin.
Also, Richard L. Gallo, et al., Arch. Dermatol., Vol. 125, pp. 502-506 (April 1989) and WO 90/09792 published Sep. 7, 1990 disclose the administration of the diuretic amiloride and its analogs as a topical agent for the treatment of ACD, particularly mice sensitized with 2,4,6-trinitrobenzene.
Despite these efforts and the knowledge gained regarding the cause of ACD, there remains a need to develop compositions which effectively prevent the onset of ACD in a person who has been sensitized to an agent, as for example a transdermally administered agent such as a drug.
Applicants have discovered that a particular class of compounds having diuretic properties, referred to herein as potassium-sparring diuretics, achieve significant prevention against sensitization of a patient's skin. As a result, an adverse reaction of the skin to a skin-sensitizing agent such as therapeutic agents administered transdermally is prevented or minimized allowing for the administration of agents that could not previously be administered and/or have longer dosage regimens. The present invention therefore provides prevention of an adverse reaction to the skin, as well as a transdermal therapy which reduces discomfort to the patient.